Pharmacology of Respiratory System

Pharmacology of Respiratory System

 

Functional anatomy and physiology: The respiratory system [divided into upper respiratory tract (including pharynx, trachea, and bronchi) and lower respiratory tract (including bronchioles, lungs and alveoli)], is responsible for a vital physiological process known as breathing (comprising of inspiration and expiration) that occurs for the sake of tissue oxygenation. The diaphragm also possesses a pivotal role as far as the process of inspiration (or inhalation) and expiration (exhalation) is concerned.

Respiratory defense mechanism: Although the presence of an effective blood-alveolar barrier restricts the entry of blood-born pathogens into respiratory tract, the direct interaction of upper respiratory tract with environmental air favors the inhalatory route to be employed for the introduction of harmful agents (like pollutants, allergens, infectious agents etc. that are expressed as noxious stimuli, invade the respiratory tract and subsequently bring about anatomical and/or physiological alterations). To overcome this problem nature has provided the respiratory system with an efficient defense mechanism in terms of muco-ciliary apparatus and mononuclear phagocytic system (MPS). The mucus secretion (released by goblet cells, located in external nostrils) forms a protective layer over the mucous lining of the nostrils and is capable to entrap foreign particles. The upper respiratory tract is lined by pseudostratified columnar streociliated epithelium (smoking leads to progressive loss of these streocilia and hence disturbs this protective barrier). These cilia oppose the access of any foreign invader by virtue of their synchronous movement. Mononuclear phagocytic system (MPS) comprises of alveolar macrophages and intravascular macrophages that are meant for the phagocytosis (enzymatic break down) of xenobiotics.

Nervous innervation of respiratory smooth muscles

Type of efferent pathway	Receptor	Neurotransmitter	Signaling mechanism	Response
Parasympathetic (Dominant pathway which provides baseline tone of mild bronchoconstriction)	M3	Acetylcholine    (ACh)	Phospholipase C -mediated conversion of PIP2into IP3 and DAG. These second messengers increase intracellular calcium level to elicit cellular response.	Broncho-constriction
Histaminergic	H1	Histamine	Same as M3	Broncho-constriction
Sympathetic	α1	Norepinephrine	Same as M3	Broncho-constriction
	α2	Norepinephrine	Inhibition of adenyl cyclase-mediated cAMP synthesis	Reduction of parasympathetic Broncho-constriction
	β2	Norepinephrine	Activation of adenyl cyclase-mediated cAMP synthesis	Broncho-dilation
Non-adrenergic non-cholinergic (NANC)	Irritant receptors (Nose)	Vaso-active intestinal peptide (VIP)	Stimulation of vagus nerve	Reflex Broncho-dilation

Bronchodilators: These drugs restore normal bronchial caliber to improve alveolar ventilation. They are also used to reverse broncho-constriction (caused by allergic/inflammatory reaction, COPD, bronchospasm or bronchial stenosis).These agents are preferably administered through inhalatory route (in the form of nasal sprays and inhalers) and are categorized into following types.

1. Sympathomimetics (β agonists): Selective β₂ agonists [Salbutamol (Ventolin), Terbutaline and Clenbuterol] as well as non-selective β agonists (Ephedrine, Pseudoephedrine and Isoproterenol) can be used to cause bronchodilation. But non-selective β agonists are linked with undesirable cardiac stimulation that can be life-threatening in animals with pre-existing tachycardia (like supraventricular tachycardia). The detailed pharmacology and toxicology of sympathomimetics has been described in chapter-1 (ANS).

2. Muscarinic antagonists (Anticholinergics): Ipratropium, Glycopyrrolate and Atropine are capable to block M₃-mediated broncho-constriction but they should be used cautiously to prevent unwanted adverse effects.

3. Methylxanthines: This group includes both natural substances like Caffeine (found in tea, coffee), Theobromine (derived from Cocoa plant, present in chocolate and candies) and Theophylline as well as synthetic agents like Aminophylline. They act as competitive inhibitors of phosphodiesterase (PDE) enzyme which causes the intracellular degradation of cAMP (this indirect increase in the level of 2^nd messenger leads to bronchodilation). Methylxanthines also stimulate CNS, cardiac contractility, diuresis, gastric acid secretion (therefore these are contraindicated in all conditions of hyperacidity) and skeletal muscle contraction. Methylxanthines also block adenosine receptors to display a bronchodilatory effect. Primarily, Caffeine and Theobromine are used to cause CNS (cerebral cortical) stimulation while Theophylline and Aminophylline are prescribed as expectorants. Dogs are unable to properly metabolize Theobromine and commonly suffer from chocolate poisoning (there is no specific antidote to treat this intoxication). Hyperacidity, tachycardia and seizures [uncontrolled electrical activity in the brain (resulting from CNS stimulation), which may produce a physical convulsion, minor physical signs, thought disturbances, or a combination of symptoms] are possible adverse effects of Methylxanthines.

4. Leukotriene receptor antagonists: Acolade is a high affinity competitive antagonist of Leukotriene (Leukotrienes are inflammatory mediators, released in response to the entry of allergens in respiratory tract, undergo receptor occupancy and trigger leukocytic infiltration via chemotaxis) that prevents antigen-induced bronchospasm.

Pathophysiology of asthma: Asthma is a common chronic inflammatory disease of airways characterized by variable and chronic symptoms [including wheezing (continuous, coarse, whistling sound), coughing, chest tightness (bronchoconstriction), and dyspnea (shortness of breath)], reversible airflow obstruction, and bronchospasm. The pathogenesis of asthma can be summarized in the following manner.

The entry of allergens (like pollens, dust particles and animal dander) into upper respiratory tract marks the initiation of this ailment by activating the first-line defense mechanism (muco-cilliary apparatus).

Soon after the degranulation of mast cells results in the release of histamine that binds with H₁ receptors.

Membrane damage also occurs during which membrane phospholipids are subjected to enzymatic degradation by phopholipase A₂ yielding arachidonic acid that is converted to prostaglandins and leukotreins.

Infiltration of mononuclear phagocytic cells mediates chemotaxis to provoke cells that are involved in defense mechanism (e.g. leukocytes).

Histamine, prostaglandins and leukotriens are all inflammatory mediators which cause vasodilation, bronchoconstriction and alteration of membrane permeability.

During later phase the infiltration of cytokine-releasing T-cells and eosinophils further aggravate the condition by causing edema, bronchospasm and epithelial damage that ultimately lead to obstruction and collapse of airways.

Anti-asthmatic drugs: These drugs are classified into following categories.

1. H₁ receptor antagonists (Antihistaminic drugs): Chlorpheniramine (Avil), Mepheneramine (Meprasone), Cetrizine (Zyrtec), Diphenylhydramine (Benadryl) and Dimenhydrinate (Gravinate) are common members of this category. They are also termed as anti-allergic agents as they are to relieve almost all sorts of allergic reactions. Diphenylhydramine and Dimenhydrinate are also applied as anti-emetics. Sedation is the most common side effect of antihistaminic drugs.

2. Mast cell stabilizers: Cromoglycate (also known as Cromolyn) stabilizes the mast cell membrane and thus inhibits their degranulation.

3. 5-HT₂ receptor antagonists: Cyproheptadiene (basically used as appetite stimulant to treat anorexia) has been reported to be effective in feline asthma.

4. Nonsteroidal anti-inflammatory drugs: Anti-prostaglandinic effect of NSAID_S can become advantageous to suppress inflammatory symptoms associated with asthma.

5. Corticosteroids: They inhibit the synthesis of leukotriens which carry out leukocytic infiltration and chemotaxis. The pharmacology and adverse effects of NSAID_S and Corticosteroids have been discussed in detail in chapter-2.

6. Adrenergic agonists: Selective β₂ agonists [Salbutamol (Ventolin), Terbutaline and Clenbuterol] as well as non-selective β agonists (Ephedrine, Pseudoephedrine and Isoproterenol) can be used to mitigate (reduce) bronchospasm.

7. Anticholinergic drugs: Ipratropium, Glycopyrrolate and Atropine can be used to induce bronchodilation and improve alveolar ventilation.

8. Methylxanthines: Theophylline and Aminophylline are used as bronchodilators and expectorants.

Allergic rhinitis (Hay fever or pollenosis): It is an allergic inflammation of the nasal mucosa and associated airways. It occurs when allergens such as pollens or dust particles are inhaled by an individual with a sensitized immune system, and trigger antibody production. The specific antibody is immunoglobulin E (IgE) which binds to mast cells and basophils containing histamine. IgE bound to mast cells are stimulated by pollen and dust, causing the release of inflammatory mediators such as histamine (and other chemicals). This causes itching, swelling and mucus production. Inflammatory mediators favor vasodilation that causes nasal congestion (passive hyperemia) and ultimately leads to rhinorhea (running nose). Fibrosis of nasal septum may also occur in chronic cases. The two categories of allergic rhinitis include: Seasonal (occurs particularly during pollen seasons) and Perennial (occurs throughout the year) rhinitis.

Treatment of allergic rhinitis: Any of the following drugs can be used for this purpose.

1. Nasal decongestants: Phenyleprine (selective α₁ agonist) can be administered to cause peripheral vasoconstriction that will lead to redistribution of accumulated blood (and will relieve rhinorrhea). However its use should be avoided in patients with pre-existing mydriasis and glaucoma.

2. Corticosteroids: They prevent the synthesis of leukotriens which perform leukocytic infiltration and chemotaxis. In this way the help to avoid further inflammatory response.

3. H₁ receptor antagonists (Antihistaminic drugs): Similar to other allergic conditions, allergic rhinitis is also responsive to the administration of antihistaminic drugs. But they should be used cautiously as their prolonged inhalatory application (via aerosol) can lead to rhinitis medicamentosa which is characterized by stiffness of the nose.

Pathophysiology of coughing reflex: Cough is a protective mechanism for the removal of foreign particles/allergens or excessive secretion from respiratory tract. It is divided into dry cough (mediated by irritation of upper respiratory tract resulting from the entry of allergens) and productive cough (that arises for the expulsion of sputum). Therefore productive cough is considered a beneficial mechanism, is not commonly treated and is nevertheless induced through the use of expectorants. Whereas dry cough is suppressed (through the use of anti-tussive drugs) as it can damage lungs. The upper respiratory tract (pharynx, larynx and tracheo-bronchial tree) consists of chemorecptors and mechanorecptors while lower respiratory tract (lungs) contains stretch receptors that are sensitive to noxious stimuli (like allergens and excessive secretion) and transmit impulses to cough centre (located in medulla) by means of afferent/sensory nerves (like vagus nerve and glossopharyngeal nerve). The cough centre (co-ordinated with respiratory centre and vomiting centre, which are also present in medulla) analyzes the impulses and then transmits signals (via efferent/motor nerves) to thoracic, abdominal and diaphragmatic muscles for causing forceful expulsion of air from the lungs that leads to coughing.

Anti-tussives: These are drugs which are used to suppress coughing (dry cough, commonly caused by severe bronchoconstriction) that can inflict damage to the lungs.

1.      Centrally acting anti-tussive drugs: These  drugs act by depressing cough centre and are subdivided into following groups;

(a)   Opiod/Narcotic anti-tussives: Morphine, Codeine (Methyl Morphine), Hydrocodone and Hydromorphone are included in this class. They bind to opiod receptors (in CNS) and depress CNS (including cough centre located in medulla). These agents are also used to induce sedation and analgesia. They are linked with certain side effects like dependence/addiction and sedation.

(b)   Non-narcotic anti-tussives: Dextromethorphan (free from addictive potential) increases the cough threshold set by cough centre and thus it depresses coughing.

2.      Locally acting anti-tussives: These are further divided into following categories;

(a)   Demulcents: They cause soothing effect on respiratory mucosa, reduce irritation and suppress coughing. Glycerine [C₃H₅(OH)₃], Honey and Liquorice (Mulaithi) are examples of such agents.

(b)  Mucosal anesthetics: Benzotate desensitizes the pulmonary stretch receptors and blocks the sensory impulses of coughing.

(c)  Bronchodilators: Ephedrine and Theophylline can also be used to suppress coughing by relieving bronchospasm.

Expectorants (Mucokinetics; muco = mucus, kinesis = movement): These drugs enhance the flow/fluidity of airway mucus (also known as sputum) either by increasing its volume or by decreasing its viscosity and thus facilitate its removal through coughing and ciliary action. Expectorants are used to induce productive cough in case of tracheobronchitis, bronchopneumonia and COPD. Expectorants are divided into following categories.

1. Stimulant/Secretory expectorants: These are further subdivided into following types.

(a)  Direct acting stimulant expectorants: These directly stimulate the submucosal tracheobronchial glands to increase their secretion. Guaicol and Guaiphenesin (also used as skeletal muscle relaxant) are examples of such drugs.

(b)  Indirect acting (reflex acting) stimulant expectorants: They indirectly stimulate tracheobronchial glands via vagal reflex. Ipecacuanha (obtained from Cephalis ipecacuanha) is included in this class. It is basically used as emetic/nauseant but it can cause expectpration when used in sub-therapeutic doses. Most common side effects are profused salivation and lacrymation.

(c)  Mixed acting (or saline) stimulant expectorants: They utilize both mechanisms (direct and indirect) to induce mucokinesis. KI is orally given to treat chronic bronchitis but its overdosage can cause iodinism-induced goiter [excessive iodine inhibits its own active transport to thyroid follicle by saturating the transporter/carrier system. Therefore no iodination of thyroglobulin occurs inside the thyroid follicle (due to lack of iodine in the follicle) and deficient level of thyroid hormones in the blood triggers the release of thyroid stimulating hormone (TSH) from anterior pituitary gland (to stimulate thyroid glands) which facilitates the accumulation of more and more thyroglobulin in thyroid glands that leads to enlargement of thyroid glands (goiter)]. The use of KI is also contraindicated in lactating animals (as iodine will be released in milk) and pregnant animals (to avoid congenital goiter). NH₄Cl (ammonium chloride or Noshadar) and (NH₄)₂Co₃ (ammonium carbonate) are also expectorants with similar mode of action but their overdosage leads to hyperammonemia followed by dypnea and pulmonary edema.

2. Mucolytic expectorants: They cause depolymerization or hydrolysis of glycoprotein strands in mucus (called mucolysis) which leads to decline in mucus viscosity. Bromohexine and Acetylcysteine are such expectorants. Sulfhydral group of Acetylcysteine disintegrates disulfide bonds of mucus glycoproteins thus causing mucolysis. Acetylcysteine (also used as antidote of Paracetamol/Acetaminophen intoxication) is a precursor of Glutathione (anti-oxidant that arrests and inactivates reactive oxygen species (ROS) and prevents them from causing cellular damage).

3. Diluent expectorants: These agents dilute/hydrate the airway mucus and thus increase its fluidity. Steam can be used to liquefy viscous sputum but it is effective only in case of large airways (as the size of water molecules is about 10 μm which cannot penetrate inside smaller airways). Application of steam is not an easy procedure as far as animals are concerned.

4. Miscellaneous agents: 5% CO₂ is capable to cause bronchial hyperemia that is followed by expectoration. Antimony Potassium Tartrate is a nauseant expectorant that can also be used to induce productive cough. Additionally it has been found that dietary usage of chili (Capsicum annum) can cause expectoration (probably by acting as stimulant expectorant) and application of water over the head region (and even bathing) can liquefy/dilute the mucus to facilitate its removal. However the use of chili should be avoided in persons with pre-existing gastric ulcer, hyperacidity and digestive disturbances (as it can aggravate the conditions).